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Abstract Mutations in fibrillin 1 (FBN1) is the main cause of Marfan syndrome (MFS) with thoracic aortic aneurysm (TAA) as the main complication. Activation of the complement system plays a key role in the formation of thoracic and abdominal aortic aneurysms. However, the role of the complement system in MFS-associated aortic aneurysms remains unclear. In this study, we observed increased levels of complement C3a and C5a in the plasma of MFS patients and mouse, and the increased deposition of the activated complement system product C3b/iC3b was also observed in the elastic fiber rupture zone of 3-month-old MFS mice. The expression of C3a receptor (C3aR) was increased in MFS aortas, and recombinant C3a promoted the expression of cytokines in macrophages. The administration of a C3aR antagonist (C3aRA) attenuated the development of thoracic aortic aneurysms in MFS mice. The increased inflammation response and matrix metalloproteinases activities were also attenuated by C3aRA treatment in MFS mice. Therefore, these findings indicate that the complement C3a/C3aR inhibition alleviates the formation of aortic aneurysm in Marfan syndrome mice.

Abstract Along with the constantly evolving functional microsystems toward more diversification, the more rigorous design deliberation of pursuing higher mass‐loading of electrode materials and low‐temperature fabrication compatibility have imposed unprecedented demand on integrable all‐solid‐state thin‐film microbatteries. While the classic thin‐film intercalation cathode prepared by vacuum‐based techniques inevitably encountered a post‐annealing process, tape‐casting technologies hold great merits both in terms of high‐mass loading and low‐temperature processing. In this work, a novel microbattery configuration is developed by the combination of traditional tape‐casting thick electrodes and sputtered inorganic thin‐film solid electrolytes (~3 μm lithium phosphorus oxynitride). Enabled by physically pressed or vapor‐deposited Li as an anode, solid‐state batteries with tape‐casted LiFePO4 electrodes exhibit outstanding cyclability and stability. To meet integration requirements, LiFePO4/LiPON/Si microbatteries were successfully fabricated at low temperatures and found to achieve a wide operating temperature range. This novel configuration has good prospects in promoting the thin‐film microbattery enabling a paradigm shift and satisfying diversified requirements.

Objective MicroRNAs (miRNAs) are endogenous non-coding RNAs that can play a role in the post-transcriptional regulation of mammalian preadipocyte differentiation. However, the precise functional mechanism of its regulation of fat metabolism is not fully understood. Methods We identified bta-miR-365-3p, which specifically targets the 3′ untranslated region (3′UTR) of the FK506-binding protein 5 (FKBP5), and verified its mechanisms for regulating expression and involvement in adipogenesis. Results In this study, we found that the overexpression of bta-miR-365-3p significantly decreased the lipid accumulation and triglyceride content in the adipocytes. Compared to inhibiting bta-miR-36 5-3p group, overexpression of bta-miR-365-3p can inhibit the expression of adipocyte differentiation-related genes C/EBPα and PPARγ. The dual-luciferase reporter system further validated the targeting relationship between bta-miR-365-3p and FKBP5. FKBP5 mRNA and protein expression were detected by quantitative real-time polymerase chain reaction and Western blot. Overexpression of bta-miR-365-3p significantly down-regulated FKBP5 expression, while inhibition of bta-miR-365-3p showed the opposite, indicating that bta-miR-365-3p negatively regulates FKBP5. Adenosine 5′-monophosphate (AMP)-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway is closely related to the regulation of cell growth and is involved in the development of bovine adipocytes. In this study, overexpression of bta-miR-365-3p significantly inhibited mRNA and protein expression of AMPK, mTOR, and SREBP1 genes, while the inhibition of bta-miR-365-3p expression was contrary to these results. Overexpression of FKBP5 significantly upregulated AMPK, mTOR, and SREBP1 gene expression, while inhibition of FKBP5 expression was contrary to the above experimental results. Conclusion In conclusion, these results indicate that bta-miR-365-3p may be involved in the AMPK/mTOR signaling pathway in regulating Yanbian yellow cattle preadipocytes differentiation by targeting the FKBP5 gene.

Abstract Background Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. Methods We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. Results Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. Conclusions BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers. Graphical abstract

IntroductionThis study aimed to investigate the role of Nicotinamide N-methyltransferase (NNMT) in the drug sensitivity of non-small cell lung cancer (NSCLC) cells, with a focus on its impact on autophagy and resistance to the chemotherapeutic agent osimertinib. The study hypothesized that NNMT knockdown would enhance drug sensitivity by modifying autophagic processes, providing a potential new therapeutic target for overcoming chemoresistance in lung cancer.MethodsProteomic analysis was utilized to identify changes in protein expression following NNMT knockdown in H1975 and H1975 osimertinib resistance (H1975OR) lung cancer cell lines. Gene expression patterns and their correlation with NNMT expression in lung cancer patients were analyzed using The Cancer Genome Atlas (TCGA) dataset. Additionally, a predictive model for lung cancer survival was developed via lasso regression analysis based on NNMT-associated gene expression. Drug sensitivity was assessed using the IC50 values and apoptosis ratio, and autophagy was evaluated through Western blot and flow cytometric analysis.ResultsSignificant variations in the expression of 1,182 proteins were observed following NNMT knockdown, with a significant association with autophagy-related genes. Analysis of gene expression patterns unveiled a significant correlation between NNMT expression and specific changes in gene expression in lung cancer. The predictive model successfully forecasted lung cancer patient survival outcomes, highlighting the potential of NNMT-associated genes in predicting patient survival. Knockdown of NNMT reversed osimertinib resistance in H1975 cells, as evidenced by altered IC50 values and apoptosis ratio, and changes were observed in autophagy markers.DiscussionKnockdown of NNMT in lung cancer cells enhances drug sensitivity by modulating autophagy, providing a promising therapeutic target to overcome chemoresistance in NSCLC. The study underscores the importance of NNMT in lung cancer pathology and underscores its potential as a predictive marker for clinical outcomes. Additionally, the developed predictive model further supports the clinical relevance of NNMT-associated gene expression in improving the prognosis of lung cancer patients.

Current land use classification models based on very high-resolution (VHR) remote sensing images often suffer from high sample dependence and poor transferability. To address these challenges, we propose an unsupervised multisource domain adaptation framework for cross-domain land use classification that eliminates the need for repeatedly using source domain data. Our method uses the Swin Transformer as the backbone of the source domain model to extract features from multiple source domain samples. The model is trained on source domain samples, and unlabeled target domain samples are then used for target domain model training. To minimize the feature discrepancies between the source and target domains, we use a weighted information maximization loss and self-supervised pseudolabels to alleviate cross-domain classification noise. We conducted experiments on four public scene datasets and four new land use scene datasets created from different VHR images in four Chinese cities. Results show that our method outperformed three existing single-source cross-domain methods (i.e., DANN, DeepCORAL, and DSAN) and four multisource cross-domain methods (i.e., M3SDA, PTMDA, MFSAN, and SHOT), achieving the highest average classification accuracy and strong stability. We conclude that our method has high potential for practical applications in cross-domain land use classification using VHR images.

Background: Phthalates (PAEs) are endocrine-disrupting chemicals ubiquitously found in the environment. This study aimed to examine the association between exposure of PAEs and subfecundity in preconception couples. Methods: This is a nested case-control study based on preconception cohort. Preconception couples with intention to conceive were enrolled and followed up until a clinically confirmed pregnancy or 12 menstrual cycles of preparation for conception. A total of 107 couples with subfecundity- time to pregnancy (TTP) more than 12 menstrual cycles, and 144 couples ≤12 cycles were included in the analysis. The levels of PAE metabolites in one spot urine samples were detected and compared between the groups. The weighted quantile sum (WQS) regression model and Bayesian kernel machine regression (BKMR) model were used to examine the joint effects of couples’ exposure to PAEs on subfecundity. Results: Using the multivariate binary logistic regression model, compared to the lowest quartile of urinary ∑PAEs concentration group, both preconception females (aOR=2.42, 95% CI: 1.10–5.30, p=0.027) and males (aOR=2.99, 95% CI: 1.36–6.58, p=0.006) in the highest quartile group had an increased risk of subfecundity, and a dose-response relationship was observed between PAEs and the risk of subfecundity. The WQS analyses found that co-exposure to PAE mixture was a risk factor for subfecundity in preconception female (aOR=1.76, 95% CI: 1.38–2.26, p

Background Sialidosis is a rare disorder caused by mutations in the NEU1 gene located on chromosome 6p21.3, constituting a group of autosomal recessive diseases. Enzyme activity analysis, electron microscopy examination and genetic testing are reliable methods for diagnosis. Despite previous reports on the disease, its rarity means that its clinical manifestations and prognosis still warrant attention due to the limited amount of information available.Methods We report a case of a 40-year-old woman who was admitted to our hospital for worsening dysarthria of 16 years duration and facial and limb twitching that had been present for 2 years. Genetic testing was undertaken.Results Genetic testing confirmed type I sialidosis, the first reported instance of this disease in the Hainan Free Trade Port in China. The patient did not have the typical cherry-red spot in the fundus. Despite aggressive treatment, she died of status epilepticus 2 months later. This result indicates that the disease has a poor prognosis.Discussion Cherry-red spots in the fundus are characteristic features of type I sialidosis and it has been referred to as the cherry-red spot myoclonus syndrome. We hypothesise that environmental factors may also play a significant role. Overemphasis on the presence of cherry-red spots may mislead clinicians and delay diagnosis. Furthermore, patients presenting with isolated myoclonus should undergo visual evoked potential and somatosensory evoked potential tests, as well as genetic testing to confirm or rule out sialidosis.

Chikungunya virus (CHIKV) is a reemerging arbovirus causing disease on a global scale, and the potential for its epidemics remains high. CHIKV has caused millions of cases and heavy economic burdens around the world, while there are no available approved antiviral therapies to date. In this study, nifuroxazide, an FDA-approved antibiotic for acute diarrhea or colitis, was found to significantly inhibit a variety of arboviruses, although its antiviral activity varied among different target cell types. Nifuroxazide exhibited relatively high inhibitory efficiency in yellow fever virus (YFV) infection of the hepatoma cell line Huh7, tick-borne encephalitis virus (TBEV) and west nile virus (WNV) infection of the vascular endothelial cell line HUVEC, and CHIKV infection of both Huh7 cells and HUVECs, while it barely affected the viral invasion of neurons. Further systematic studies on the action stage of nifuroxazide showed that nifuroxazide mainly inhibited in the viral replication stage. In vivo, nifuroxazide significantly reduced the viral load in muscles and protected mice from CHIKV-induced footpad swelling, an inflammation injury within the arthrosis of infected mice. These results suggest that nifuroxazide has a potential clinical application as an antiviral drug, such as in the treatment of CHIKV infection.

This paper presents a method of calculating and correcting grinding face gears on an internal gear grinding machine. The generating principle of face gears is studied, and the feasibility of grinding motion on an internal gear grinding machine is analyzed. Then, the motions that need to be followed for grinding are analyzed based on the gear machine tool structure. Four main error sources causing tooth surface deviation in the grinding movements are proposed. The mathematical modeling of the grinding of face gears containing proposed error sources on an internal gear grinding machine is accurately established. The influence of the error sources on the topological deviations of the tooth surface is explored. A sensitivity matrix is established for the influence of various error factors on the tooth surface deviations. The correction values of each error factor are obtained in the case of existing tooth surface deviations. Finally, a virtual machining experiment is conducted, which proves the accuracy of the proposed method for characterizing grinding and realizing corrections.

The FHD-2B proton magnetometer at Wen’an station had large F component noise from 2020 to 2021. There is a high correlation between noise interference and temperature, which is generally characterized by high noise in winter and low noise in summer. The surrounding environment, power supply voltage, grounding resistance, power supply line leakage, probe leakage and power frequency interference of the magnetic room were checked respectively, and no interference sources were found. By studying the principle of FHD proton magnetometer, it is found that the harmonic capacitance capacity of FHD proton magnetometer changes with temperature. The capacity is small at low temperature and large at high temperature. The change of the capacity of the harmonic capacitor will affect the center frequency of the oscillation circuit f0, resulting in increased noise. Since the noise interference of the FHD proton magnetometer at Wen’an station is highly correlated with temperature, it is speculated that the noise interference may be related to the change in the capacity of the harmonic capacitance. We can adjust the inductance L of the probe to correct the influence of the circuit center frequency of the harmonic capacitance capacity transformation. The probe inductance was adjusted several times through experiments, and 34.4 mH was selected as the most appropriate probe inductance value. After the experiment, the noise value of F component decreased, the data curve became smooth, and the noise interference was solved.

Abstract Background Venetoclax (Ven) combined with intensive chemotherapy was proven effective in the management of acute myeloid leukemia (AML). However, the severe and prolonged myelosuppression remains a concern to worry about. To explore more appropriate combination regimens, we designed Ven combining daunorubicin and cytarabine (DA 2 + 6) regimen as induction therapy, aimed to evaluate the effectiveness and safety in adults de novo AML. Methods A phase 2 clinical trial was performed in 10 Chinese hospitals to investigate Ven combined with daunorubicin and cytarabine (DA 2 + 6) in patients with AML. The primary endpoints were overall response rate (ORR), comprising of complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), and partial response (PR). Secondary endpoints included measurable residual disease (MRD) of bone marrow assessed by flow cytometry, overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and the safety of regimens. This study is a currently ongoing trial listed on the Chinese Clinical Trial Registry as ChiCTR2200061524. Results Overall, 42 patients were enrolled from January 2022 to November 2022; 54.8% (23/42) were male, and the median age was 40 (range, 16–60) years. The ORR after one cycle of induction was 92.9% (95% confidence interval [CI], 91.6–94.1; 39/42) with a composite complete response rate (CR + CRi) 90.5% (95% CI, 89.3–91.6, CR 37/42, CRi 1/42). Moreover, 87.9% (29/33) of the CR patients with undetectable MRD (95% CI, 84.9–90.8). Grade 3 or worse adverse effects included neutropenia (100%), thrombocytopenia (100%), febrile neutropenia (90.5%), and one mortality. The median neutrophil and platelet recovery times were 13 (5–26) and 12 (8–26) days, respectively. Until Jan 30, 2023, the estimated 12-month OS, EFS, and DFS rates were 83.1% (95% CI, 78.8–87.4), 82.7% (95% CI, 79.4–86.1), and 92.0% (95% CI, 89.8–94.3), respectively. Conclusion Ven with DA (2 + 6) is a highly effective and safe induction therapy for adults with newly diagnosed AML. To the best of our knowledge, this induction therapy has the shortest myelosuppressive period but has similar efficacy to previous studies.

Mineralogical evidence of water–rock interactions is a strong indicator of the presence of liquid water on ancient Mars. Previous observations have found widely distributed hydrated minerals in the southern highlands, whereas such discoveries have been rare in the younger northern lowlands. China’s first Mars exploration mission successfully landed a rover (Zhurong) in southern Utopia Planitia, providing an opportunity to analyze the exposed rocks in the northern lowlands. Using data from the short-wave infrared (SWIR) spectrometer and the laser-induced breakdown spectrometer (LIBS) onboard the Zhurong rover, we found evidence for the widespread presence of hydrated minerals (probably sulfates or silica) around the landing site. The basaltic-like elemental compositions of the targeted samples further indicated that hydrated minerals are likely minor components. The results from Zhurong suggest that active aqueous activities occurred during the overall cold and dry Amazonian era on Mars. However, further evaluations are needed on the duration and scale of these activities.

Highlights The all-solid-state thin-film Li-S battery has been successfully developed by stacking VGs-Li2S cathode, lithium-phosphorous-oxynitride (LiPON) solid electrolyte, and Li anode. The obtained VGs-Li2S thin-film cathode exhibits excellent long-term cycling stability (more than 3,000 cycles), and an exceptional high temperature tolerance (up to 60 °C). The superb electrochemical performance can be attributed to the favorable compatibility and outstanding interfacial stability between VGs-Li2S thin film and LiPON.

Background: There are six widely used equations to calculate the estimated glomerular filtration rate (eGFR) of patients. We aimed to assess the predictive power of preoperative eGFR calculated by these equations for the occurrence of postoperative acute kidney injury (AKI). Methods: Patients who underwent isolated coronary surgery from January 2016 to January 2021 were continuously enrolled. Serum creatinine and cystatin C used to calculate eGFR were both measured within 1 week before surgery. The eGFR was calculated using six equations: Cockcroft Gault (CG) equation, Chinese abbreviated modification of diet in renal disease (MDRD) equation, chronic kidney disease-epidemiology (CKD-EPI) equation, and full age spectrum (FAS) equation. Postoperative AKI was diagnosed by Kidney Disease Improving Global Outcomes criteria (KDIGO) (① urine volume

Abstract Background Lung cancer incidence and mortality remain high and are now the leading cause of cancer‐related death. Lung adenocarcinoma (LUAD) is one of the main histological subtypes of lung cancer. Previous studies have shown the role of inflammation in the development of lung cancer, but the relationship between cytokines and LUAD is still unclear. To further differentiate and explore the association of cytokines with the risk of non‐invasive and invasive LUAD, we studied and assessed serum cytokine levels in patients with two types of LUAD. Methods A cohort study of 90 non‐invasive LUAD and 90 invasive LUAD was retrospectively included, and the clinical characteristics were recorded in detail. The differences in the levels of 12 serum cytokines (IFN‐α, IFN‐γ, IL‐10, IL‐12P70, IL‐17A, IL‐1β, IL‐2, IL‐4, IL‐5, IL‐6, IL‐8, and TNF‐α) between the two groups of patients with LUAD were analyzed and evaluated. And we evaluated the clinical value of cytokine differential diagnosis of invasive LUAD based on receiver operating characteristics (ROC) curves. Results The mean age of the patients was 56.6 years, and the proportions of males and females were 38.9% and 61.1%, respectively. IFN‐α, IL‐1β, IL‐2, IL‐6, TNF‐α, IL‐4, and IL‐8 were significantly increased in patients with invasive LUAD compared with the non‐invasive LUAD group. Further research found that smoking is an important factor, with changes in the four cytokines IL‐1β, IL‐6, IL‐8, and TNF‐α being significantly higher in the smoking group of patients with invasive LUAD. It can be seen from the area under the curve that IL‐1β and IL‐2 have a significant differential diagnosis. Conclusions We observed differences in preoperative serum cytokine levels between patients with invasive and non‐invasive LUAD, which may serve as potential serum biomarkers for clinical differential diagnosis and disease progression assessment.

AbstractClimate change and human activities have altered the water environment and affected the community structure of aquatic organisms. Few studies have focused on the specific responses of multiple aquatic organisms, and their interactions, to environmental factors, particularly in urban wetland ecosystems. To address this gap, this study aimed to investigate the effects of seasonal variation and water connectivity on water properties and aquatic organisms in the Xixi wetland in Zhejiang Province, China. The results demonstrated that water properties showed significant differences with changes in the season and water connectivity, and the species richness, Shannon-Wiener index, Simpson diversity and Pielou evenness of aquatic organisms varied seasonally in riverways and ponds. Meanwhile, the response of various organisms to environmental factors was inconsistent. Dissolved oxygen and suspended solids greatly influenced phytoplankton, while water temperature was the principal factor affecting the diversity of zooplankton and benthic organisms. The partial least squares path model revealed that water properties had a significant direct positive effect on the diversity of the phytoplankton community, while it had a distinct direct negative effect on zooplankton community. Environmental factors influenced the diversity of benthic organisms through a trade-off way: directly through a significant negative effect on the benthic organisms, and through a significant positive effect on the phytoplankton, further influencing the benthic community in a significantly positive way. This study highlights the understanding of the patterns and underlying mechanisms of freshwater aquatic biodiversity, and the interaction of phytoplankton, zooplankton and benthic organisms to water environmental factors in freshwater ecosystems.

The local population is considered one of the main stakeholders in tourism development. Understanding whether and how road and transport infrastructure is related to local communities' overall attitude toward tourism development is crucial. Scholars have suggested that the overall positive attitude of a local community is associated with its tourism development. This study keeps in view the positive and negative consequences of road and transport development and its relationship with local communities' overall attitude. Drawing on social exchange theory, this study investigates local community support for tourism development using 565 samples from the local community of Gilgit-Baltistan and northern areas of Pakistan. Findings show that community visibility and image enhancement are positively related to the overall attitude of the local community. Infrastructure and urbanization are also positively related to the host community's overall attitude, whereas traffic problems are negatively related to the overall attitude of the local community. However, environmental concerns have an insignificant relationship with the overall attitude of the local community. Overall attitude of local communities is also positively related to support for tourism development. Furthermore, economic benefits positively moderate the relationship between the overall attitude of the local community and its support for tourism development.

Abstract Background Soil salinization and alkalization are widespread environmental problems that limit grapevine (Vitis vinifera L.) growth and yield. However, little is known about the response of grapevine to alkali stress. This study investigated the differences in physiological characteristics, chloroplast structure, transcriptome, and metabolome in grapevine plants under salt stress and alkali stress. Results We found that grapevine plants under salt stress and alkali stress showed leaf chlorosis, a decline in photosynthetic capacity, a decrease in chlorophyll content and Rubisco activity, an imbalance of Na+ and K+, and damaged chloroplast ultrastructure. Fv/Fm decreased under salt stress and alkali stress. NPQ increased under salt stress whereas decreased under alkali stress. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment showed the differentially expressed genes (DEGs) induced by salt stress and alkali stress were involved in different biological processes and have varied molecular functions. The expression of stress genes involved in the ABA and MAPK signaling pathways was markedly altered by salt stress and alkali stress. The genes encoding ion transporter (AKT1, HKT1, NHX1, NHX2, TPC1A, TPC1B) were up-regulated under salt stress and alkali stress. Down-regulation in the expression of numerous genes in the ‘Porphyrin and chlorophyll metabolism’, ‘Photosynthesis-antenna proteins’, and ‘Photosynthesis’ pathways were observed under alkali stress. Many genes in the ‘Carbon fixation in photosynthetic organisms’ pathway in salt stress and alkali stress were down-regulated. Metabolome showed that 431 and 378 differentially accumulated metabolites (DAMs) were identified in salt stress and alkali stress, respectively. L-Glutamic acid and 5-Aminolevulinate involved in chlorophyll synthesis decreased under salt stress and alkali stress. The abundance of 19 DAMs under salt stress related to photosynthesis decreased. The abundance of 16 organic acids in salt stress and 22 in alkali stress increased respectively. Conclusions Our findings suggested that alkali stress had more adverse effects on grapevine leaves, chloroplast structure, ion balance, and photosynthesis than salt stress. Transcriptional and metabolic profiling showed that there were significant differences in the effects of salt stress and alkali stress on the expression of key genes and the abundance of pivotal metabolites in grapevine plants.

Background Themucosal structure of the respiratory tract is similar to that of the gastrointestinal tract in humans, which is the body's first line of defense against the invasion of pathogens through the function of mucosal barrier. When the respiratory tract infection stimulates the airway mucosa to produce a local immune response, it affects the intestinal tract through migration and homing, resulting in the weakening of the local mucosal anti-infection ability, inducing mucosal barrier damage, and further aggravating chronic obstructive pulmonary disease (COPD) . Objective To explore the effects of Bufei Jianpi Formula on the expression levels of inflammatory factors in lung tissue, and the content of lung-gut related peptides in lung and colon tissues in a rat model of stable COPD based on a typical viscera theory of Traditional Chinese Medicine, namely "the lungs and large intestines are interior-exteriorly related" . Methods This experiment was carried out from September 2019 to December 2020. Fifty SPF SD rats were selected, and equally and randomly divided into control, model, Bufei Jianpi, aminophylline and probiotics groups. Except for the control group, the rats in other groups received cigarette smoke exposure combined with intranasal instillation of lipopolysaccharide (LPS) in the first eight weeks of intervention for establishing a COPD model. From the ninth week of intervention, rats in the control and model groups received intragastric administration of 0.9% sodium chloride solution, and those in Bufei Jianpi, aminophylline and probiotics groups received intragastric administration of Bufei Jianpi Formula, aminophylline and probiotics, respectively. The rats were sacrificed after 12 weeks of intervention. The pathological changes of lung and colon tissues were observed under an optical microscope, the expression levels of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in lung tissue were detected by immunohistochemistry. The contents of secretory immunoglobulin A (SIgA) in bronchoalveolar lavage fluid (BALF) , substance P (SP) and vasoactive intestinal peptide (VIP) in lung and colon tissues were detected by enzyme-linked immunosorbent assay (ELISA) . Results In terms of morphology, the lung and colon tissue structures of rats in the control group were basically intact. In the model group, the trachea was narrowed and surrounded by a lot of inflammatory cells with thickened bronchial wall. The improvement in histopathology of the lung tissues was the most obvious in Bufei Jianpi group. The colon tissue of rats in the model group was damaged, which was manifested by numerous shed epithelial cells, and crypts in different shapes and sizes. Bufei Jianpi group demonstrated better improvement in histopathology of the colon tissue. There were statistically significant differences in the expression levels of TNF-α, IL-10, SP and VIP in the lung tissue of the five groups of rats (FTNF-α=70.640, FIL-10=8.444, FSP=108.700, FVIP=4.665, P

Abstract Background The study aimed to observe the effects of a Twinlight laser on the titanium surface proliferation of inflammatory Mesenchymal stem cells (MSCs), inflammatory cytokine expression, and osteogenic differentiation. Methods The MSCs were collected from bone tissue of healthy individuals.The cellular inflammatory model was established with 1 μg/mL lipopolysaccharide (LPS).Under the cellular inflammatory model,divided into five groups: the normal control group (C); the inflammatory control group (L); Er:YAG laser group (L + E); Nd:YAG laser group (L + N); Er:YAG laser and Nd:YAG laser group (L + E + N). The treated cells were inoculated onto titanium disks.The normal and inflammatory MSCs on the surface of titanium surface were examined by CCK-8, scanning election microscopy (SEM), quantitative real-time polymerase chain reaction (qRT‑PCR) and other methods for their proliferation, growth pattern, expression of inflammatory factors Interleukin-6 (IL-6), Interleukin-8 (IL-8) and osteogenic genes Runx2 (Runt-related transcription factor 2) and alkaline phosphatase (ALP), providing the theoretical basis and experimental data for the Twinlight laser-assisted treatment of peri-implantitis. Statistical analyses were performed using a Student's t test with SPSS 17.0 software. Results Through observation using SEM, the cell densities of the L + E + N, L + E, and L + N groups were similar, but cell bodies in the L + E + N group were fuller and each had more than two pseudopodia. The expression level of IL-6 mRNA in the L, L + N, L + E, and L + E + N groups was higher than in group C (P 0.05). On day 7, the expression level of RUNX2 mRNA in the L + E + N group was higher than in group L (P

Abstract Background The unripe fruits of Rubus chingii Hu. (“Fu-peng-zi” in Chinese) is a well-known herbal tonic in traditional Chinese medicine (TCM) for tonifying liver and kidney. However, little is known regarding its therapeutic efficacy against liver fibrosis and the underlying mechanism. Methods The current research aims to explore the potential of Rubus chingii Hu. unripe fruits extract (RF) in the treatment of liver fibrosis and explore the underlying mechanism. RF was administered (450 and 900 mg·kg− 1 of body weight per day) orally to male C57BL/6 mice with CCl4-induced liver fibrosis for 3 weeks. The histopathological changes and fibrosis stage in liver tissue were assessed using hematoxylin and eosin (H&E) and Sirius red staining. The distribution of α-SMA and Col1A1 in the liver was analyzed to determine the hepatic stellate cells (HSCs) activation using immunohistochemistry and immunofluorescent analysis. Various biochemical markers in serum (ALT, AST) and liver (Hyp, IL1-β, IL6, TNF-α and MCP-1) were observed to assess the liver’s injury, fibrosis, and inflammation. In liver tissue, fibrosis-associated proteins including α-SMA, TGF-β1, Smad2/3, p-Smad2/3, and Smad4 were detected through a Western blot assay. Pyrosequencing-based analysis of bacterial 16 S ribosomal RNA from variable regions V3–V4 of fecal samples characterized the gut microbiota. Spearman’s rank correlation analysis was performed for the association between altered bacterial genera by RF and pharmacodynamics parameters. Results Three weeks of RF treatment can significantly lower liver inflammatory levels, pathological abnormalities, and collagen fibrous deposition in mice with CCl4-induced liver fibrosis. The expressions of α-SMA and Col1A1 were lowered by RF, while the expression levels of TGF-β/Smads signaling pathway-related proteins, including TGF-β1, p-Smad2/3, and Smad4, were dramatically decreased by RF. The RF treatment significantly increased or reduced 18 different bacterial species, restoring the CCl4-induced gut microbiota imbalance to the normal group’s levels. According to correlation analysis, the bacterial genera Bifidobacterium and Turicibacter were the most significant in restoring CCl4-induced liver fibrosis. Conclusions RF can reduce liver damage and delay the onset of liver fibrosis through modulating TGF-β/Smads signaling pathway. Furthermore, RF’s anti-liver fibrosis effect was related to balancing the gut microbial community, partly attained by increasing Bifidobacterium and Turicibacter in liver fibrosis.

Abstract Acute myeloid leukemia (AML) is a malignant disorder derived from neoplastic myeloid progenitor cells characterized by abnormal proliferation and differentiation. Although novel therapeutics have recently been introduced, AML remains a therapeutic challenge with insufficient cure rates. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies including acute lymphoblastic leukemia (ALL). However, the application of CAR-T cells appears to be challenging due to the enormous molecular heterogeneity of the disease and potential long-term suppression of hematopoiesis. Here we report on the generation of CD33-targeted CAR-modified natural killer (NK) cells by transduction of blood-derived primary NK cells using baboon envelope pseudotyped lentiviral vectors (BaEV-LVs). Transduced cells displayed stable CAR-expression, unimpeded proliferation, and increased cytotoxic activity against CD33-positive OCI-AML2 and primary AML cells in vitro. Furthermore, CD33-CAR-NK cells strongly reduced leukemic burden and prevented bone marrow engraftment of leukemic cells in OCI-AML2 xenograft mouse models without observable side effects.

Abstract Objective To explore the role of genetic testing of VKORC1 and CYP2C9 in determining the dosage of warfarin after aortic valve replacement. Methods A total of 172 patients receiving warfarin after aortic valve replacement were divided into a control group (n = 86) and an experimental (n = 86) group based on acceptance of genetic testing. In the experimental group, three loci of VKORC1 and CYP2C9 were tested by polymerase chain reaction-restriction fragment length polymorphism technique, and the initial dose of warfarin was determined based on the genetic testing results and warfarin oral-dose table recommended by U.S. Food and Drug Administration (FDA). In the control group, warfarin (3 mg per night) was used as the initial dose. The international normalized ratio (INR) of each patient was continuously monitored after medication. The percentages of patients meeting the target INR in the two groups at specific time points and at 3-month follow-up after discharge from the hospital were monitored, and the incidence of various adverse events was compared between the groups. Results Based on the results of genetic testing, 68 patients received 3–4 mg/d (79.1%), 10 patients received 0.5–2 mg/d (11.6%), and eight patients received 5–7 mg/d (9.3%) as the initial dosages of warfarin in the experimental group. The percentages of the patients meeting the target INR on the third and sixth day of postoperative medication were 45.3% and 73.3%, respectively, in the experimental group, and 29.8% and 58.3%, respectively, in the control group. The INR critical values during hospitalization occurred in 2.3% in the experimental group and in 7.1% in the control group, while the percentage of the patients meeting the target INR after 3 months was 86.1% in the experimental group and 83.1% in the control group. Conclusion Genetic testing may guide the selection of the initial dose of warfarin after heart valve replacement to rapidly achieve a stable dose.

IntroductionParameterizing the process of trees from the comfort zone to mortality during progressive drought is important for, but is not well represented in, vegetation models, given the lack of appropriate indices to gauge the response of trees to droughts. The objective of this study was to determine reliable and readily available tree drought stressindices and the thresholds at which droughts activate important physiological responses.MethodsWe analyzed the changes in the transpiration (T), stomatal conductance, xylem conductance, and leaf health status due to a decrease in soil water availability (SWA), predawn xylem water potential (ψpd), and midday xylem water potential (ψmd) in Robinia pseudoacacia seedlings during progressive drought.ResultsThe results showed that ψmd was a better indicator of drought stress than SWA and ψpd, because ψmd was more closely related to the physiological response (defoliation and xylem embolization) during severe drought and could be measured more conveniently. We derived the following five stress levels from the observed responses to decreasing ψmd: comfort zone (ψmd > -0.9 MPa), wherein transpiration and stomatal conductance are not limited by SWA; moderate drought stress (-0.9 to -1.75 MPa), wherein transpiration and stomatal conductance are limited by drought; high drought stress (-1.75 to -2.59 MPa), wherein transpiration decreases significantly (T< 10%) and stomata closes completely; severe drought stress (-2.59 to -4.02 MPa), wherein transpiration ceases (T< 0.1%) and leaf shedding orwilting is > 50%; and extreme drought stress (< -4.02 MPa), leading to tree mortality due to xylem hydraulic failure.DiscussionTo our knowledge, our scheme is the first to outline the quantitative thresholds for the downregulation of physiological processes in R. pseudoacacia during drought, therefore, can be used to synthesize valuable information for process-based vegetation models.

Abstract The past several decades have witnessed great progress in high‐performance field effect transistors (FET) as one of the most important electronic components. At the same time, due to their intrinsic advantages, such as multiparameter accessibility, excellent electric signal amplification function, and ease of large‐scale manufacturing, FET as tactile sensors for flexible wearable devices, artificial intelligence, Internet of Things, and other fields to perceive external stimuli has also attracted great attention and become a significant field of general concern. More importantly, FET has a unique three‐terminal structure, which enables its different components to detect external mechanics through different sensing mechanisms. On one hand, it provides an important platform to shed deep insights into the underlying mechanisms of the tactile sensors. On the other hand, these properties could in turn endow excellent components for the construction of tactile matrix sensor arrays with high quality. With special emphasis on the configuration of FETs, this review classified and summarized structure‐optimized FET tactile sensors with gate, dielectric layer, semiconductor layer, and source/drain electrodes as sensing active components, respectively. The working principles and the state‐of‐the‐art protocols in terms of high‐performance tactile sensors are detail discussed and highlighted, the innovative pixel distribution and integration analysis of the transistor sensor matrix array concerning flexible electronics are also introduced. We hope that the introduction of this review can provide some inspiration for future researchers to design and fabricate high‐performance FET‐based tactile sensor chips for flexible electronics and other fields.

Abstract Yes-associated protein (YAP) activation is crucial for tumor formation and development, and its stability is regulated by ubiquitination. ISGylation is a type of ubiquitination like post-translational modification, whereas whether YAP is ISGylated and how ISGylation influences YAP ubiquitination-related function remains uncovered. In addition, YAP can activate glucose metabolism by activating the hexosamine biosynthesis pathway (HBP) and glycolysis, and generate a large number of intermediates to promote tumor proliferation. However, whether YAP stimulates the pentose phosphate pathway (PPP), another tumor-promoting glucose metabolism pathway, and the relationship between this stimulation and ISGylation needs further investigation. Here, we found that YAP was ISGylated and this ISGylation inhibited YAP ubiquitination, proteasome degradation, interaction with-beta-transducin repeat containing E3 ubiquitin-protein ligase (βTrCP) to promote YAP stability. However, ISGylation-induced pro-YAP effects were abolished by YAP K497R (K, lysine; R, arginine) mutation, suggesting K497 could be the major YAP ISGylation site. In addition, YAP ISGylation promoted cell viability, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor formation. YAP ISGylation also increased downstream genes transcription, including one of the key enzymes of PPP, 6-phosphogluconolactonase (6PGL). Mechanistically, YAP promoted 6PGL transcription by simultaneously recruiting SMAD family member 2 (SMAD2) and TEA domain transcription factor 4 (TEAD4) binding to the 6PGL promoter to activate PPP. In clinical lung adenocarcinoma (LUAD) specimens, we found that YAP ISGylation degree was positively associated with 6PGL mRNA level, especially in high glucose LUAD tissues compared to low glucose LUAD tissues. Collectively, this study suggested that YAP ISGylation is critical for maintaining its stability and further activation of PPP. Targeting ISGylated YAP might be a new choice for hyperglycemia cancer treatment.

In contrast to T lymphocytes, natural killer (NK) cells do not require prior sensitization but are rapidly activated upon encountering virally infected or neoplastic cells. In addition, NK cells can be safely applied in an allogeneic setting, making them important effector cells for the development of off-the-shelf therapeutics for adoptive cancer immunotherapy. To further enhance their therapeutic potential, here, we engineered continuously expanding NK-92 cells as a clinically relevant model to express a humanized second-generation chimeric antigen receptor (CAR) with a composite CD28-CD3ζ signaling domain (hu14.18.28.z) that targets the disialoganglioside GD2, which is expressed at high levels by neuroblastoma cells and other tumors of neuroectodermal origin. In a separate approach, we fused an IL-15 superagonist (RD-IL15) to the GD2-CAR via a P2A processing site. Lentivirally transduced NK-92/hu14.18.28.z and NK-92/hu14.18.28.z_RD-IL15 cells both displayed high and stable CAR surface expression and specific cytotoxicity toward GD2-positive tumor cells. GD2-CAR NK cells carrying the RD-IL15 construct in addition expressed the IL-15 superagonist, resulting in self-enrichment and targeted cell killing in the absence of exogenous IL-2. Furthermore, co-culture with RD-IL15-secreting GD2-CAR NK cells markedly enhanced proliferation and cytotoxicity of bystander immune cells in a paracrine manner. Our results demonstrate that GD2-CAR NK cells co-expressing the IL-15 superagonist mediate potent direct and indirect antitumor effects, suggesting this strategy as a promising approach for the further development of functionally enhanced cellular therapeutics.

Ternary organic solar cells (OSCs) have attracted intensive studies due to their promising potential for attaining high-performing photovoltaics, whereas there has been an opening challenge in minimizing the open circuit voltage (Voc) loss while retaining the optimal carrier extraction in the multiple mixture absorbers. Here, we systemically investigate a ternary absorber comprised of two acceptors and a donor, in which the resultant Voc and fill factor are varied and determined by the ratios of acceptor components as a result of the unbalance of non-radiative recombination rates and charge transport. The transient absorption spectroscopy and electroluminescence techniques verify two distinguishable charge-transfer (CT) states in the ternary absorber, and the mismatch of non-radiative recombination rates of those two CT states is demonstrated to be associated with the Voc deficit, whilst the high-emissive acceptor molecule delivers inferior electron mobility, resulting in poor charge transport and a subpar fill factor. These findings enable us to optimize the mixture configuration for attaining the maximal-performing devices. Our results not only provide insight into maximizing the photovoltage of organic solar cells but can also motivate researchers to further unravel the photophysical mechanisms underlying the intermolecular electronic states of organic semiconductors.

Background: Liver fibrosis is a dysregulated wound-healing process in response to diverse liver injuries, and an effective drug therapy is not yet available. Genistein, which is one of the most active natural flavonoids mainly derived from soybean products (e.g., Cordyceps sinensis mycelium), exhibits various biological effects, including hepatoprotective and anti-inflammatory properties. However, the anti-hepatic fibrosis mechanisms of genistein are poorly understood. The aim of our research is to explore the effect and the possible mechanism of genistein against liver fibrosis. Materials and methods: Cell counting kit-8, EdU, and flow cytometry assays were applied to evaluate the effects of genistein on cell viability, proliferation, and cell cycle arrest in human hepatic stellate cell (HSC) line LX2 cells. HSC activation was induced by transforming growth factor-β1 in LX2 cells and liver fibrosis model was established by the intraperitoneal injection of dimethylnitrosamine (DMN) in rats to assess the anti-fibrosis effects of genistein in vivo and in vitro models. HSC activation was assessed by qRT-PCR, Western blot, immunohistochemistry, and immunofluorescent assay. Liver injury and collagen deposition were evaluated by histopathological assay, serum biochemistry, and hepatic hydroxyproline content assays. The mRNA expressions of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and inflammation related-factors were assessed by qRT-PCR assay. Furthermore, the functional properties of macrophage in the liver were assessed by immunohistochemistry assay. The expression levels of the JAK2/STAT3/SOCS3 signaling pathway related-protein were assessed by Western blot analysis. Results: Genistein significantly inhibited cell viability and proliferation and induced cell cycle arrest at G0/G1 phase in LX2 cells, respectively. Furthermore, oral administration of genistein significantly ameliorated liver injury and the collagen deposition in rats with DMN-induced fibrosis model. Genistein suppressed the expression levels of HSC activation marker α-smooth muscle actin and collagen type I alpha 1 in vivo and in vitro. Genistein significantly decreased the mRNA expression levels of extracellular matrix degradation genes MMP2/9 and TIMP1 in rats. Genistein alleviated the mRNA expression levels of IL-1β, IL-6, TNF-α, and MCP-1 and regulated the protein expressions of CD68, CD163, and CD206 in the liver. Moreover, genistein attenuated the expressions of p-JAK2/JAK2, p-STAT3/STAT3, and SOCS3 protein both in vivo and in vitro. Conclusion: Taken together, our results showed that genistein could be improved liver fibrosis both in vivo and in vitro, probably through regulating the functional properties of macrophage and inhibiting the JAK2/STAT3/SOCS3 signaling pathway.

ObjectiveThis study aimed to evaluate the clinical therapeutic efficacy of anti-snake venom serum blockade in treating local tissue necrosis caused by Chinese cobra (Naja atra) bites.MethodsPatients bitten by a Chinese cobra (Naja atra) (n = 50) that met the inclusion criteria were randomly divided into two groups: the experimental group (n = 25) and the control group (n = 25). The experimental group received regular as well as anti-snake venom serum blocking treatment, whereas regular treatment plus chymotrypsin blocking therapy was given to the control group. The necrotic volumes around snake wounds in these groups were detected on the first, third and seventh days. On the third day of treatment, some local tissues in the wounds were randomly selected for pathological biopsy, and the necrosis volume of the local tissue was observed. Furthermore, the amount of time required for wound healing was recorded.ResultsOn the third and seventh days post-treatment, the necrotic volume of the wound of the experimental group was much smaller than that of the control group, and the experimental group's wound healing time was shorter than that of the control group (all p < 0.05). Moreover, the pathological biopsies taken from the control group showed nuclear pyknosis, fragmentation, sparse nuclear density, and blurred edges, and the degree of necrosis was much higher than that of the experimental group.ConclusionsAnti-snake venom blocking therapy is a new and improved therapy with good clinical effect on local tissue necrosis caused by Chinese cobra bites; moreover, it is superior to conventional chymotrypsin blocking therapy in the treatment of cobra bites. It can better neutralize and prevent the spread of the toxin, reduce tissue necrosis, and shorten the course of the disease by promoting healing of the wound. Furthermore, this treatment plan is also applicable to wound necrosis caused by other snake toxins, such as tissue necrosis caused by elapidae and viper families.Clinical trial registrationThis trial is registered in the Chinese Clinical Trial Registry, a primary registry of International Clinical Trial Registry Platform, World Health Organization (Registration No. ChiCTR2200059070; trial URL:http://www.chictr.org.cn/edit.aspx?pid=134353&htm=4).

PurposeThe purpose of this study is to examine the relationships between organizational commitment and turnover intention, and to test the mediating effect of perceived insider status, and moderating effect of gender on that relationship.MethodologyData were collected using a questionnaire survey method from 820 temporary employees of government agencies working in China. The data obtained were analyzed according to the moderated mediation.FindingsAs a result of the analysis, it was determined that perceived insider status has a partial mediation effect on the relationship between organizational commitment and turnover intention. Also, the results supported the moderated mediation and showed that the indirect effect of organizational commitment and turnover intention through perceived insider status was weaker for males than females. Then, the theoretical and practical implications of the findings are discussed.

Coxsackievirus B (CVB) is one of the major viral pathogens of human myocarditis and cardiomyopathy without any effective preventive measures; therefore, it is necessary to develop a safe and efficacious vaccine against CVB. Immunoinformatics methods are both economical and convenient as in-silico simulations can shorten the development time. Herein, we design a novel multi-epitope vaccine for the prevention of CVB by using immunoinformatics methods. With the help of advanced immunoinformatics approaches, we predicted different B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes, respectively. Subsequently, we constructed the multi-epitope vaccine by fusing all conserved epitopes with appropriate linkers and adjuvants. The final vaccine was found to be antigenic, non-allergenic, and stable. The 3D structure of the vaccine was then predicted, refined, and evaluated. Molecular docking and dynamics simulation were performed to reveal the interactions between the vaccine with the immune receptors MHC-I, MHC-II, TLR3, and TLR4. Finally, to ensure the complete expression of the vaccine protein, the sequence of the designed vaccine was optimized and further performed in-silico cloning. In conclusion, the molecule designed in this study could be considered a potential vaccine against CVB infection and needed further experiments to evaluate its safety and efficacy.

Cholestatic liver disease (CLD) is a chronic liver disease characterized by ductular reaction, inflammation and fibrosis. As there are no effective chemical or biological drugs now, majority of CLD patients eventually require liver transplantation. Astragali radix (AR) is commonly used in the clinical treatment of cholestatic liver disease and its related liver fibrosis in traditional Chinese medicine, however its specific active constituents are not clear. Total astragalus saponins (ASTs) were considered to be the main active components of AR. The aim of this study is to investigate the improvement effects of the total astragalus saponins (ASTs) and its main constituents in cholestatic liver disease. The ASTs from AR was prepared by macroporous resin, the content of saponins was measured at 60.19 ± 1.68%. The ameliorative effects of ASTs (14, 28, 56 mg/kg) were evaluated by 3, 5-Diethoxycarbonyl-1, 4-dihydrocollidine (DDC)-induced CLD mouse model. The contents of hydroxyproline (Hyp), the mRNA and protein expression of cytokeratin 19 (CK19) and α-smooth muscle actin (α-SMA) in liver tissue were dose-dependently improved after treatment for ASTs. 45 astragalus saponins were identified in ASTs by UHPLC-Q-Exactive Orbitrap HRMS, including astragaloside I, astragaloside II, astragaloside III, astragaloside IV, isoastragaloside I, isoastragaloside II, cycloastragenol, etc. And, it was found that ductular reaction in sodium butyrate-induced WB-F344 cell model were obviously inhibited by these main constituents. Finally, the improvement effects of astragaloside I, astragaloside II, astragaloside IV and cycloastragenol (50 mg/kg) were evaluated in DDC-induced CLD mice model. The results showed that astragaloside I and cycloastragenol significantly improved mRNA and protein expression of CK19 and α-SMA in liver tissue. It suggested that astragaloside I and cycloastragenol could alleviate ductular reaction and liver fibrosis. In summary, this study revealed that ASTs could significantly inhibit ductular reaction and liver fibrosis, and astragaloside I and cycloastragenol were the key substances of ASTs for treating cholestatic liver disease.

Abstract Diabetes is an important risk factor for liver cancer, but its mechanism is unknown. Corosolic acid (CA) has been proven to have both hypoglycemic and antitumor effects, so revealing the function of CA can help us understand the relationship between diabetes and liver cancer. In previous studies, we confirmed that CA can effectively inhibit the expression of YAP, an important oncoprotein in HCC cells, and the proliferation of HCC cells. In addition, we also found that O-GlcNAcylation plays an indispensable role in HCC tumorigenesis. However, it is not clear whether CA can inhibit the effect of O-GlcNAcylation on HCC cells. In this study, the antitumor ability of CA was investigated by inhibiting the O-GlcNAcylation level and its corresponding mechanism. The results showed that HG (high glucose) could promote the proliferation of liver cancer cells, while CA could inhibit cell growth under HG conditions and tumor growth in a xenotransplantation model. CA can inhibit the activation of the HBP pathway and reduce the expression of YAP and OGT under HG conditions. Importantly, we found that CA can reduce YAP expression and O-GlcNAcylation by inhibiting the activity of CDK19. Overexpression of CDK19 partially reversed the CA-induced decrease in YAP and O-GlcNAcylation. This is the first evidence that CA can reduce the proliferative capacity of cells with high glucose levels and further inhibit tumor growth by inactivating the CDK19/YAP/O-GlcNAcylation pathway, suggesting that CA is a candidate drug for the development of treatments against diabetes-associated liver cancer.

Abstract As "molecular bridge," coupling agents can not only realize the covalent connection of composites, but also affect their properties, thus affecting the properties of devices based on them. Herein, leveraging differences in charge conduction properties of the (3‐aminopropyl)trimethoxysilane and 5,10,15,20‐tetrakis(4‐aminophenyl)‐21H,23H‐porphine caused by conjugacy structural differences, two kinds of layer‐by‐layer assembled smart carbon materials with different electrical properties are obtained at the same reduction temperature. The two graphene ultrathin films are then “planted” on Si/SiO2 substrates, respectively, as semiconductor layer and source/drain electrodes to fabricate an ultra‐stable all‐graphene field effect transistor (AG‐FET). Enabled by the covalent functionalized configuration and the functionally diverse of coupling agents, the AG‐FET obtained by this simple method won the high electrical characteristics, the hole, electron mobility, and the shelflife could reach 3.79 cm2/(V·s), 3.78 cm2/(V·s), and 18 months, respectively. In addition, good material stability and excellent device structure endow the device exceptional stability, electrical stability, and solvent resistance, improving its application prospect in solution phase sensing/detection. Such characteristics could be used to sense, transduce, and respond to external stimuli, especially in solution phase to monitor the important analytes, such as Hg2+ in a flowing sewage environment. We believe that such easy‐to‐manufacture AG‐FETs with ultrahigh performance and ultrahigh stability could also show great application prospects in other significant fields.

Magnetite nanoparticles (Fe3O4-NPs)/orange peel (MOP) composite was prepared via one-step in-situ co-precipitation method as magnetic heterogeneous Fenton-like catalyst. The properties of MOP were characterized by scanning electron microscopy, transmission electron microscopes, Brunauer–Emmett–Teller, X-ray diffraction, Fourier-transform infrared, thermogravimetric analysis and X-ray photoelectron spectroscopy technologies. Its Fenton-like catalytic responses towards removal of methyl orange (MO) were investigated, in which the effects of initial dye concentration, pH, temperature and hydrogen peroxide dosage were studied. The MO degradation ratio up to 98.0% was obtained within 20 min in optimized conditions. The catalyst showed excellent catalytic stability exhibiting nearly 90% degradation ratio in the 10th cycle within 20 min, whereas pure Fe3O4-NPs showed only 62.5% in this stage. Due to the stabilization of complexing orange peel hydroxyl to iron oxide in the composite and its magnetic separation property, MOP composite exhibits excellent Fenton-like catalytic performance, which offers great prospects for low-cost and high-efficiency organic dye wastewater treatment. Highlights Cheap raw materials like waste biomass and common Fe salts.; Fe3O4/orange peel composite as heterogeneous Fenton-like catalyst.; 98.0% of 30 ppm MO can be degraded within 20 min in optimized conditions.; Easy separation: fast magnetic separation from aqueous solution within 1 min.; Superior cycle catalytic stability: MO (20 ppm) degradation ratio reaches up to nearly 90% within 20 min in the 10th cycle.;

Coxsackievirus B (CVB), a member of Enterovirus genus of Picornaviridae, is the leading pathogen of viral myocarditis and dilated cardiomyopathy. The pathogenesis of CVB-induced myocarditis has not been completely elucidated, and no specific antiviral measurement is available presently. Circular RNAs (circRNAs) have been reported to be able to modulate viral replication and infection through bridging over non-coding RNAs (ncRNAs) and coding messenger RNAs (mRNAs). To date, the role of circRNAs in CVB infection is largely unknown. In this study, we found that hsa_circ_0076631 (circ_0076631) significantly promoted CVB type 3 (CVB3) replication. Further study showed that the underneath mechanism was circ_0076631 indirectly interacting with CVB3 through sponging miR-214-3p, which targeted the 3D-coding region of CVB3 genome to suppress viral translation. Knocking down circ-0076631 caused a suppression of CVB3 infection; thus, circ-0076631 may be a potential target for anti-CVB therapy.

Endoplasmic reticulum-associated degradation (ERAD) is a key cellular process for degrading misfolded proteins. It was well known that an asparagine (N)-linked glycan containing a free α1,6-mannose residue is a critical ERAD signal created by Homologous to α-mannosidase 1 (Htm1) in yeast and ER-Degradation Enhancing α-Mannosidase-like proteins (EDEMs) in mammals. An earlier study suggested that two Arabidopsis homologs of Htm1/EDEMs function redundantly in generating such a conserved N-glycan signal. Here we report that the Arabidopsis irb1 (reversal of bri1) mutants accumulate brassinosteroid-insensitive 1–5 (bri1–5), an ER-retained mutant variant of the brassinosteroid receptor BRI1 and are defective in one of the Arabidopsis Htm1/EDEM homologs, AtEDEM1. We show that the wild-type AtEDEM1, but not its catalytically inactive mutant, rescues irb1-1. Importantly, an insertional mutation of the Arabidopsis Asparagine-Linked Glycosylation 3 (ALG3), which causes N-linked glycosylation with truncated glycans carrying a different free α1,6-mannose residue, completely nullifies the inhibitory effect of irb1-1 on bri1-5 ERAD. Interestingly, an insertional mutation in AtEDEM2, the other Htm1/EDEM homolog, has no detectable effect on bri1-5 ERAD; however, it enhances the inhibitory effect of irb1-1 on bri1-5 degradation. Moreover, AtEDEM2 transgenes rescued the irb1-1 mutation with lower efficacy than AtEDEM1. Simultaneous elimination of AtEDEM1 and AtEDEM2 completely blocks generation of α1,6-mannose-exposed N-glycans on bri1-5, while overexpression of either AtEDEM1 or AtEDEM2 stimulates bri1-5 ERAD and enhances the bri1-5 dwarfism. We concluded that, despite its functional redundancy with AtEDEM2, AtEDEM1 plays a predominant role in promoting bri1-5 degradation.

The present study aimed to identify key circRNAs and pathways associated with heat stress in blood samples of Holstein cows, which will provide new insights into the molecular mechanisms driving heat stress in cows. Hence, we evaluated changes in milk yield, rectal temperature, and respiratory rate of experimental cows between heat stress (summer) and non-heat stress (spring) conditions with two comparisons, including Sum1 vs. Spr1 (same lactation stage, different individuals, 15 cows per group) and Sum1 vs. Spr2 (same individual, different lactation stages, 15 cows per group). Compared to both Spr1 and Spr2, cows in the Sum1 group had a significantly lower milk yield, while rectal temperature and respiratory rate were significantly higher (p < 0.05), indicating that cows in the Sum1 group were experiencing heat stress. In each group, five animals were chosen randomly to undergo RNA-seq. The results reveal that 140 and 205 differentially expressed (DE) circRNAs were screened in the first and second comparisons, respectively. According to the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, these DE circRNAs were mainly enriched in five signaling pathways, including choline metabolism, the PI3K/AKT signaling pathway, the HIF-1 signaling pathway, the longevity-regulating pathway, and autophagy. Then, we obtained the top 10 hub source genes of circRNAs according to the protein–protein interaction networks. Among them, ciRNA1282 (HIF1A), circRNA4205 (NR3C1), and circRNA12923 (ROCK1) were enriched in multiple pathways and identified as binding multiple miRNAs. These key circRNAs may play an important role in the heat stress responses of dairy cows. These results provide valuable information on the involvement of key circRNAs and their expression pattern in the heat stress response of cows.

Abstract Background Epicardial adipose tissue (EAT) shares the same microcirculation with coronary arteries through coronary arteries branches, and contributes to the development of atherosclerosis. MicroRNAs (miRNAs) are involved in the formation of atherosclerosis. However, the alteration of miRNA profile in EAT during atherosclerosis is still uncovered. Methods The miRNA expression profiles of EAT from non-coronary atherosclerosis disease (CON, n = 3) and coronary atherosclerosis disease (CAD, n = 5) patients was performed to detect the differentially expressed miRNA. Then the expression levels of miRNA in other CON (n = 5) and CAD (n = 16) samples were confirmed by realtime-PCR. miR-200b-3p mimic was used to overexpress the miRNA in HUVECs. The apoptosis of HUVECs cells was induced by H2O2 and ox-LDL, and detected by Annexin V/PI Staining, Caspase 3/7 activity and the expression of BCL-2 and BAX. Results 250 miRNAs were differentially expressed in EAT from CAD patients, which were associated with metabolism, extracellular matrix and inflammation process. Among the top 20 up-regulated miRNAs, the expression levels of miR-200 family members (hsa-miR-200b/c-3p, miR-141-3p and miR-429), which were rich in endothelial cells, were increased in EAT from CAD patients significantly. Upregulation of miR-200 family members was dependent on the oxidative stress. The overexpression of miR-200b-3p could promote endothelial cells apoptosis under oxidative stress by targeting HDAC4 inhibition. Conclusions Our study suggests that EAT derived miR-200b-3p promoted oxidative stress induced endothelial cells damage by targeting HDAC4, which may provide a new and promising therapeutic target for AS.

Abstract Background Childhood overweight and obesity (OWO) has become a major public concern worldwide including in Shanghai, one of the most developed areas of China. Understanding perceptions and challenges of tackling childhood OWO among caregivers of children is critical to provide services in need. Methods A qualitative descriptive study including in-depth interviews with seven parents and six focus group discussions with a total of 32 parents or grandparents of children zero to 6 years of age. Participants lived in three districts of Shanghai and indexed children included both those with OWO or non-OWO children. Data were analyzed using qualitative thematic analysis. Results Caregivers tended to underestimate children’s weight status, and to regard chubby children as a sign of good parental care. Some caregivers even suggested that there were positive effects of childhood overweight. Caregivers identified a number of challenges to prevention of OWO in children, including difficulties in controlling dietary intake or increasing children’s physical activities; discordant views between parents and grandparents, and barriers to accessing professional guidance. Caregivers desired more detailed advice regarding children’s nutrition intake and physical activity, and preferred online approaches. Conclusions Misconceptions regarding childhood overweight were found in caregivers of children in Shanghai. Professional guidance on childhood weight control for caregivers is desired via digital applications such as mobile phone applications and social media.

Abstract Objective To observe the changes of F waves on electrocardiograms (ECGs) in patients with persistent atrial fibrillation during the insertion of a peripherally inserted central catheter (PICC), and to analyze the application effect of the ECG method (through F wave changes) for guiding PICC tip positioning. Methods Seventy‐two patients who met the inclusion criteria and needed a PICC catheter were selected as the research subjects. We observed waveforms in the ECGs when the tip of the catheter reached a predetermined position. The chest X‐ray results were used as the gold standard to calculate the sensitivity and specificity, and judge the safety and accuracy of ECG‐guided PICC tip positioning in patients with atrial fibrillation. Results Of the 72 patients, there was no significant difference between the ECG method and chest X‐ray results (χ2 = 0.2, p > 0.05). Sixty‐one patients had F wave changes on ECG and 10 had no obvious changes (X‐ray results confirmed that five patients had a tip position that was too shallow, two had ectopic tip positions, and three were located in the correct place). The sensitivity of the method was 95.7% and the specificity was 80%. Conclusion As the ECG baselines of patients with persistent atrial fibrillation were difficult to judge and the F wave was irregular, we found that the F wave was significantly higher than before catheter insertion and fell back while withdrawing the catheter, so the catheter should be fed until the F wave significantly increased as the correct position of the catheter tip.

Background Impaired muscle regeneration and increased muscle fibrosis are observed in aged muscle accompanied by progressive loss of muscle mass (sarcopenia). However, the underlying mechanism is still unclear. Methods The differentiated expressed genes in young and aged muscles after acute injury by cardiotoxin were identified by RNA‐sequence analysis. Single‐cell RNA‐sequence analysis was used to identify cell clusters and functions in young muscle after acute injury, and flow cytometry analysis and sorting were used to validate the function. The proliferation and differentiation functions of satellite cells were accessed by immunostaining with 5‐ethynyl‐2′‐deoxyuridine and embryonic myosin heavy chain (eMyHC), respectively. Muscle regeneration ability was accessed by histopathological and molecular biological methods. Results Gene expression patterns associated with responses to interferon‐gamma (IFN‐γ) (15 genes; false discovery rate

The food and package delivery workforce in China has grown substantially in the past decade. However, delivery drivers face volatile and stressful work conditions, which can give rise to high turnover and burnout. Past research has indicated that job demands and resources (JD-R) significantly predict burnout. Scholars have also found evidence that mindfulness may be a protective factor against negative outcomes like burnout. Using data collected from 240 food and package delivery drivers in Beijing, China, we examined the effects of JD-R on burnout and whether these relations were moderated by mindfulness. Estimates produced by regression analyses indicated that job demands (JD) have significantly positive effects on burnout (β = 0.33), while job resources (JR) have a significant negative effect on burnout (β = −0.32). Mindfulness significantly moderated the effects of JD and JR on burnout (β = −1.64 and − 1.30, respectively). Results suggest that mindfulness is a protective factor for delivery drivers. Practice and policy implications are discussed.

ABSTRACT Purpose: To investigate the underlying mechanism of hepatic sinusoidal obstruction syndrome (HSOS) induced by Gynura segetum by measuring autophagy in mouse models. Methods: The model group was administered G. segetum (30 g/kg/d) by gavage, while the normal control group was administered an equal volume of saline daily for five weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic histopathological examinations, and Masson staining were performed to evaluate liver injury. Liver intercellular adhesion molecule-1 (ICAM-1) and P-selectin were evaluated by immunohistochemistry. Hepatocellular apoptosis was assessed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Protein expression levels of autophagy markers were measured using Western blot analysis. Results: Gynura segetum was found to significantly induce liver injury compared with control mice, as evidenced by the increase of serum transaminases, a decrease in triglyceride levels, and histopathological changes in mice. Gynura segetum remarkably induced hepatocellular apoptosis and upregulated the expressions of ICAM-1 and P-selectin and also downregulated the protein expression levels of LC3, Atg12 and cytoplasmic polyadenylation element binding protein. Conclusions: Our results suggested that G. segetum induced liver injury with HSOS, and it was partly due to its ability to impair the autophagy pathway.

The generation and expansion of functionally competent NK cells in vitro is of great interest for their application in immunotherapy of cancer. Since CD33 constitutes a promising target for immunotherapy of myeloid malignancies, NK cells expressing a CD33-specific chimeric antigen receptor (CAR) were generated. Unexpectedly, we noted that CD33-CAR NK cells could not be efficiently expanded in vitro due to a fratricide-like process in which CD33-CAR NK cells killed other CD33-CAR NK cells that had upregulated CD33 in culture. This upregulation was dependent on the stimulation protocol and encompassed up to 50% of NK cells including CD56dim NK cells that do generally not express CD33 in vivo. RNAseq analysis revealed that upregulation of CD33+ NK cells was accompanied by a unique transcriptional signature combining features of canonical CD56bright (CD117high, CD16low) and CD56dim NK cells (high expression of granzyme B and perforin). CD33+ NK cells exhibited significantly higher mobilization of cytotoxic granula and comparable levels of cytotoxicity against different leukemic target cells compared to the CD33− subset. Moreover, CD33+ NK cells showed superior production of IFNγ and TNFα, whereas CD33− NK cells exerted increased antibody-dependent cellular cytotoxicity (ADCC). In summary, the study delineates a novel functional divergence between NK cell subsets upon in vitro stimulation that is marked by CD33 expression. By choosing suitable stimulation protocols, it is possible to preferentially generate CD33+ NK cells combining efficient target cell killing and cytokine production, or alternatively CD33− NK cells, which produce less cytokines but are more efficient in antibody-dependent applications.

Psychological well-being indicates individuals’ positive psychological functioning and well-being. A growing body of literature, largely based on adults and old people, suggests that volunteering and charitable donations are related to individuals’ psychological well-being. As emerging adulthood is a vital time for lifespan development, the aim of this study is to examine the effects of volunteering and charitable donation on individuals’ psychological well-being on college students. Relying on theories of altruism and the warm-glow theory, this study estimates the relationships among hours of volunteering, amount of charitable donations, and psychological well-being from 1,871 Chinese college students. The linear regression results indicate that students’ hours of volunteering and the amount of charitable donations in the past year were positively associated with their psychological well-being. Volunteering, compared to charitable donations, had a slightly stronger association with psychological well-being. This study provides a rationale for academic institutions to integrate social service activities into the curriculum as a potential tool to promote students’ psychological well-being.

Abstract The pioneering exfoliation of monolayer tungsten diselenide has greatly inspired researchers toward semiconducting applications. WSe2 belongs to a family of transition‐metal dichalcogenides. Similar to graphene, WSe2 and analogous dichalcogenides have layered structures with weak van der Waals interactions between two adjacent layers. First, the readers are presented with the fundamentals of WSe2, such as types, morphologies, and properties. Here, we report the characterization principles and practices such as microscopy, spectroscopy, and diffraction. Second, the methods for obtaining high‐quality WSe2, such as exfoliation, hydrothermal and chemical vapor deposition, are briefly listed. With advantages of light weight, flexibility, and high quantum efficiency, 2D materials may have a niche in optoelectronics as building blocks in p‐n junctions. Therefore, we introduce a state‐of‐the‐art demonstration of heterostructure devices employing the p‐type WSe2 semiconductor. The device architectures include field‐effect transistors, photodetectors, gas sensors, and photovoltaic solar cells. Due to its unique electronic, optical, and energy band properties, WSe2 has been increasingly investigated due to the conductivity of the p‐type charge carrier upon palladium contact. Eventually, the dynamic research on WSe2 and van der Waals heterostructures is summarized to arouse the passion of the 2D research community.